N- and O-Substituted 4-[2-(Diphenylmethoxy)-Ethyl]-1-[(Phenyl)Methyl]Piperdine Analogs and Methods of Treating CNS Disorders Therewith

ABSTRACT

N- and O-substituted 4[2-diaromaticmethoxy and methylamino)alkyl]piperidines exhibit high CNS activity with respect to the dopamine transporter (DAT) and serotonin transporter (SERT). Preferred compounds exhibit highly differential behavior as between the DAT and SERT and between the DAT and the norepinephrine transporter (NET). The compounds have utility in treating CNS disorders, including but not limited to cocaine addiction, depression, and Parkinson&#39;s disease.

TECHNICAL FIELD

The present invention pertains to novel pharmacologically active compounds which exhibit activity for monoamine transporter systems, specifically for the dopamrine transporter (“DAT”), serotonin transporter (“SERT”), and norepinephrine transporter (“NET”). The novel compounds exhibit a high differential in activity for the DAT relative to the SERT.

BACKGROUND OF THE INVENTION

The dopamine transporter is a presynaptically located macromolecule which plays an important role in pathophysiocological processes in the central nervous system (CNS). The DAT terminates dopaminergic neurotransmission by reaccumulation of released dopamine into presynaptic neurons, M. J. Kuhar, “Neurotransmitter Uptake: A Tool in Identifying Neurotransmitter Specific Pathways”, LIFE SCI., 13, 1623-34, 1973. In cocaine addiction, binding of cocaine to the DAT and consequent blockage of dopamine uptake appears to be related to the reinforcing properties of the drug. M. E. A. Reith et al., “Structural Requirements for Cocaine Congeners to Interact With Dopamine and Serotonin Uptake Sites in Mouse Brain and to Induced Stereotyped Behavior”, BIOCHEM. PHARMACOL., 1986, 35, 1123-1129; M. C. Ritz et al., “Cocaine Inhibition of Ligand Binding At Dopamine, Norpinephrine and Serotonin Transporters: A Structure-Activity Study”, LIFE. SCI., 1990, 46, 635-645; M. C. Ritz et al., “Cocaine Receptors On Dopamine Transporters Are Related to Self-Administration of Cocaine”, SCIENCE, 1987, 237, 1219-1223; B. Giros et al., “Hyperlocomotion and Indifferenrce to Cocaine and Amphetamine in Mice Lacking the Dopamine Transporter”, NATURE, 1996, 379, 606-612. Also associated with the transport function is concentration of neurotoxic chemicals in dopaminergic neurons which is implicated in Parkinson's disease. The transporter macromolecule may be a marker for Parkinson's, H. Shoemaker et al., NAUNYN SCHMIEDEBERGS ARCH. PHARMACOL., 1985, 329, 227-235 and J.-M. Maloteaux et al., EUR. J. PHARM., 1988, 156, 331-340, as evidenced by its absence in tissue sections of Parkinson's diseased putamen. H. B. Niznik et al., ARCH. BIOCHEM. BIOPHYS., 1990, 276, 424-432 and M. J. Kaufman et al., SYNAPSE, 1991, 9, 43-49. Consequently, potent yet selective ligands for the DAT have potential for in vivo monitoring of primary targets of cocaine in the brain, for characterization of cocaine binding sites, for pharmacotherapeutic agents for treatment of cocaine addition, and for monitoring of Parkinson's Disease.

Cocaine is known to bind to various neurotransporter systems in the brain, M. E. A. Reith et al., op. cit., but the reinforcing effect of cocaine which is a factor in cocaine addition, is believed to be initiated by binding to the DAT, causing inhibition of dopamine transport. Phencyclidine (PCP), a psychoactive drug of abuse, is also known to exhibit at least some of its behavioral effects through binding to the DAT. K. M. Johnson, “Phencyclidine: Behavioral and Biochemical Evidence Supporting a Role For Dopamine”, FED. PROC., 1983, 42, 2579-2583; E. D. French et al., “Phencyclidine Binding Sites in the Nucleus Accumbens and Phencyclidine-Induced Hyperactivity are Decreased Following Lesions of the Mesolimbic Dopamine System”, EUR. J. PHARCOL., 1985, 116, 1-9. The DAT further plays a crucial role in the neurotoxic action of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MOP) which induces idiopathic Parkinson's syndrome in humans. J. Langston et al., MPTP: Current Concepts and Controversies”, CLIN. N EUROPHARMAC., 1986, 9, 485-507; H. Kinemuchi et al., “The Neurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and its Relevance to Parkinson's Disease”, NEUROCHEM. INT., 1987, 11, 359-373. The serotonin transporter (SERT) is also implicated in numerous neurological processes. For example, SERT is strongly implicated in depression and drug addiction.

Several classes of compounds have been developed to characterize cocaine and PCP binding sites at the DAT. M. E. A. Reith et al., op. cit., F. I. Carroll et al., “Cocaine Receptor: Biochemical Characterization and Structure-Activity Relationship of Cocaine Analogues at the Dopamine Transporter”, J. M ED. CHEM., 1992, 35, 969-981; R. A. Millius et al., “Synthesis and Receptor Binding of N-substituted Tropane Derivatives”, “High Affinity Ligands For Cocaine Receptor”, J. MED. CHEM., 1991, 34, 1728-1731; I. Chaudieu et al., “Role of the Aromatic Group in the Inhibition of Phencyclidine Binding and Dopamine Uptake by PCP Analogs”, PHARMACOL. BIOCHEM. BEHAV., 1989, 32, 699-705. Extensive structure-activity relationship (SAR) studies of cocaine analogs resulted in the development of potent and selective tropane derivatives which bind to the DAT. Some well known compounds of this class include CFT (Win 35,428) and RTI-55. The similarity of the structures of these tropane derivatives and cocaine is readily apparent.

More recent reports describe yet more potent and selective tropanes, P. C. Meltzer et al., “Substituted 3-phenyltropane Analogs of Cocaine: Synthesis, Inhibition of Binding At Cocaine Recognition Sites, and Positron Emission Tomography Imaging”, J. MED. CHEM., 1993, 36, 855 -862; F. I. Carroll et al., “Cocaine and 3β-(4′-substituted phenyl)tropane-2β-carboxylic acid ester and amide analogues. New High-affinity and Selective Compounds for the Dopamine Transporter”, J. MED. CHEM., 1995, 38, 379-388. In similar fashion, modification of PCP led to development of more potent analogs, I. Chaudieu et al., “Role of the Aromatic Group in the Inhibition of Phencyclidine Binding and Dopamine Uptake By PCP Analogs”, PHARMACOL. BIOCHEM. BEHAV., 1989, 32, 699-705; and J. Vignon et al., “[³H]N-[1-(2-Benzo(b)thienyl)cyclohexyl]piperidine([³H]BTCP): A New Phencyclidine Analog Selective for the Dopamine Uptake Complex”, EUR. J. PHARMCOL., 1988, 148, 427-436.

The “GBR” class of compounds, P. Van der Zee et al., “Aryl 1,4-dialk(en)ylpiperazines as Selective and Very Potent Inhibitors of Dopamine Uptake”, EUR. J. MED. CHEM, 1980, 15, 363-370, are known for their unusually high selectivity and potency for the DAT.

Two of these, with R═F and R═H, have affinities in the low nanomolar range. P. H. Anderson, “Biochemical and Pharmacological Characterization of [³H]GBR 12935 Binding in Vitro to Rat Striatal Membranes: Labeling of the Dopamine Uptake Complex”, J. NEUROCHEM., 1987, 48, 1887-1896; P. H. Anderson, “The Dopamine Uptake Inhibitor GBR 12909: Selectivity and Molecular Mechanism of Action”, EUR. J. PHARMACOL., 1989, 166, 493-504. An extensive structure/activity relationship (SAR) study produced several very potent compounds for the DAT. C. DeVries et al., “Heteroaromatic Analogs of 1-[2-(diphenylmethoxy)ethyl]- and 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazines (GBR 12935 and GBR 12909) as High-Affinity Dopamine Reuptake Inhibitors”, J. MED. CHEM., 1997, 40, 705-716; D. Matecka et al., “Development of Novel, Potent, and Selective Dopamine Reuptake Inhibitors Through Alteration of the piperazine Ring of 1-[2-(diphenylmethoxy)ethyl]- and 1-[2-[Bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazines (GBR 12935 and GBR 12909)”, J. MED. CHEM., 1996 39, 4704-4716. Radiolabeling of these compounds has facilitated elucidation of neuropharmacological activity. The GBR with R═F dissociates very slowly from the DAT, R. B. Rothman, “Tight Binding Dopamine Reuptake Inhibitors as Cocaine Antagonists”, FEBS LETT., 1989, 257, 341-344 and attenuates increase in extracellular dopamine levels induced by cocaine as measured by microdialysis. R. B. Rothman, op. cit.; U. Sogaard et al., “A Tolerance Study of Single and Multiple Dosing of the Selective Dopamine Uptake inhibitor GBR 12909 in Healthy Subjects”, INT. CLIN. PSYCHOPHARM., 1990, 5, 237-251. This compound was non-stimulatory in human volunteers, J. R. Glowa et al., “The Effects of GBR 12909 on Responding of Rhesus Monkeys Maintained Under Schedules of Cocaine- and Food-Delivery”, NIDA. RES. MONOGR., 1994, 141, 12, and has recently been shown to block cocaine self-administration behavior in the rhesus monkey. A. K. Dutta et al., “Positional Importance of the Nitrogen Atom in Novel Piperidine Analogs of GBR 12909: Affinity and Selectivity for the Dopamine Transporter”, MED. CHEM. RES., 1993, 3, 209-222. Such studies raise the possibility that suitable compounds may serve as cocaine antagonists without being themselves addictive.

SUMMARY OF INVENTION

The present invention pertains to N- and O-versions of 4-[2-diarylamino or oxoalkyl]piperidine derivatives which exhibit neuropharmacological activity with respect to the DAT, the SERT, and/or the NET. Preferred compounds of this class exhibit low nanomolar activity with respect to the DAT, and high differential binding activity with respect to the DAT compared with that for the SERT and for the NET.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates one synthesis scheme and the structures of certain of the subject invention compounds;

FIG. 2 illustrates a further synthesis scheme and the structures of certain of the subject invention compounds;

FIG. 3 illustrates a further synthesis scheme and the structures of certain of the subject invention compounds; and

FIG. 4 illustrates a further synthesis scheme and the structures of certain of the subject invention compounds.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The compounds of the present invention correspond to the formula:

wherein A is

and B is

and where X is selected from the group consisting of —NH—, —NR⁴—, —S— and —O—, R⁴ is C₁₋₄ alkyl, NH₂, C₁₋₄ hydroxyalkyl, halogenated C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ hydroxyalkenyl, halogenated C₂₋₄ alkenyl, C₂₋₄ and alkynyl, and C₂₋₄ halogenated alkynyl,

Y is —H or —OH;

1 is 0, 1, or 2, preferably 0 or 1, more preferably 0; n is 1 or 2, preferably 2; m is 1 or 2, preferably 1; o is 0, 1, 2, 3, or 4, preferably 0, 1, or 2, most preferably 0 or 1; p is 0, 1, 2, 3, or 4, preferably 0, 1, or 2, most preferably 0 or 1; q is 0, 1, 2, or 3, preferably 0 or 1; R, R¹, and R² are selected from the group consisting of H, F, Cl, CN, COOEt, OH, NO₂, NH₂, OR⁵, wherein R⁵ is C₁₋₈ alkyl, C₅₋₆ cycloalkyl, or C₂₋₈ alkenyl or R² is a 5 or 6 membered heterocycle, preferably a heterocycle selected from the group consisting of:

wherein R⁶ may be C₁₋₄ alkyl, substituted or unsubstituted phenyl or naphthyl, it being understood that the hydroxyl group is not substituted onto an ethylenic carbon.

The compounds of the present invention also include those of the formula:

where A, B, R, and o are defined as above.

In the above formulae, A and B are preferably

where p is 1 or 2. In the above formula, when m is 2 or 3, one of the methylene hydrogens may be substituted by OR⁷ where R⁷ is alkyl, preferably C₁₋₁₆ alkyl, more preferably C₁₋₄ lower alkyl, or C₂₋₁₈ alkylene, or

where R⁸ is C₁₋₁₈ alkyl or C₂₋₁₈ alkylene.

Preferably, the compounds of the formula (I) correspond to

The present invention does not include compounds falling within structural Formula I or its preferred subset, when the following conditions are met:

-   When A is phenyl, X is O, Y is H, l is 0, m=1, and n is 1,     -   R, R¹ and R² are not all H when B is phenyl; and     -   R and R¹ are not both F when B is phenyl; -   When A is phenyl, X is O, Y is H, l is 0, m=1, and n=z,     -   when R² and R¹ are both H and B is phenyl, R² is not halo,         methoxy, methyl, nitro, or amino when q is 1, and is not         3-chloro-4-fluoro when q is 2;     -   when R and R¹ are 4-fluoro, B is not an unsubstituted phenyl;     -   when R is 4-halo, B is phenyl, and q is 1, R² is not F; -   When A is phenyl, X is O, Y is H, l is 0, n is 2, m is 2, and B is     unsubstituted phenyl,     -   when o and p are both 1, R and R¹ are not both halo;     -   when A is phenyl, l is 0, n is 2, and m is 2, at least one of R,         R¹, and R² is other than H; -   When A is phenyl, B is phenyl, X is O, Y is H, l is 0, m is 2, l is     2, and q is 0, R and R¹ are not both methyl; -   When A is phenyl, X is O, Y is H, B is phenyl, l is 0, m is 2, and n     is 1, not all of R, R¹, and R² are H,     -   when r is O and o and p are 1, R and R¹ are not both 4-fluoro; -   When A is phenyl, X is O, Y is H, l is 0, m is 3, and n is 2,     -   when B is phenyl, q is 1, and R² is H, o and p are not both         zero,     -   when B is phenyl, o and p are not both 1 when R and R¹ are both         4-halo or are both methoxy; -   When X is O, Y is H, o is 0 and A is unsubstituted phenyl, l is 0, m     is 3, and n is 2, B is not 4-fluorophenyl or a 6 membered heteroaryl     ring bonded to the (CH₂)_(m) group at the 3-ring position; -   When X is O, Y is H, A is unsubstituted thiophenyl, l is 0, m is 3,     n is 2, Y is H, and B is unsubstituted phenyl, o is other than 0 but     is not 1 when R is 4-fluoro; -   When X is O, Y is H, A is unsubstituted thiophenyl, o is 0, l is 0,     m is 1, and 1 is 2, B is not phenyl, 3-pyridyl, or 4-(fluorophenyl). -   When X is O, Y is H, A is unsubstituted phenyl, l is 0, m is 1, and     n is 2, B is not unsubstituted thiophenyl or unsubstituted     2,3-benzothiophenyl. -   When X is NH, Y is H, A is phenyl, l is 0, m is 1, and n is 2,     -   when q is 0, o is 1 and p is 1, R and R¹ are not both 4-fluoro,     -   when q is 1, o is 0 and p is 0, B is not 4-(fluorophenyl).

The compounds of the present invention also include those having the structure

wherein A is defined as before and may also be COOCH₃, ═O, CH₃, F, or OH; X is O, S, NH, NR⁹ or N— where the remaining valence of N with Z forms a ring structure; r is 0-8, preferably 0-4, and more preferably 0, 1, or 2, Z is H or C₁₋₄ alkylene, preferably H or C₁₋₂ alkylene, the alkylene groups, when present, forming ring structure with X when X is N—, and B is as defined previously, or is H, CH₃, —CH═CH₂, and R⁹ is

wherein R¹⁰ is C₆₋₂₀ alkyl. Preferred compounds of this structure include those where A is substituted phenyl, X is NH, Z is H, and B is substituted phenyl, and those where X is N—, r is 0 and Z is —CH₂CH₂—, or —CH₂CH₂CH₂—, forming a six or seven membered ring including both nitrogens.

Examples of structural formulae encompassed by the above definition are the following where R² group shown represents one or more than one R², preferably one or two R² groups, which may occupy any ring position:

wherein in the latter two compounds, X is preferably NH or O.

Preferred compounds are those where substituents on the N-arylalkyl moiety are electronegative and electron withdrawing groups. In particular, compounds having the structural formulae

have been shown to provide unexpectedly low activity in the nanomolar range, as well as high selectivity as shown by the difference in binding affinities with respect to the DAT and SERT. In the foregoing formulae, each variant is considered as individually defined. The various replacement groups for X, and R through R⁵ may be employed to the exclusion of any one or more than one of such replacements.

Further preferred classes of active compounds include those of structural Formula I where B is a phenyl group bearing a 4-cyano, 4-iodo, or 3,4-difluoro-group, and in particular, compounds falling within the scope of structural Formula I or its preferred subgeneric general formula, and corresponding to the following structures:

Most preferably, the active compounds of the invention correspond to compounds of the formula:

where B¹ is 4-cyanophenyl, 3,4-difluorophenyl, or 4-iodophenyl. In each of the more general structures above having a —(CH₂)_(m)— radical, when m is 2 or 3, any of the carbons of the —(CH₂)_(m)— moiety may be substituted by —R⁷ as defined above.

Further examples of preferred compounds include:

where R′″ is H, OH, NH₂, OR⁹, or NHR⁹ where R⁹ is

where R¹⁰ is C₆₋₂₀ alkyl, and

All the various geometric and stereoisomers of the subject invention compounds are useful. However, some geometric and stereoisomers have unexpectedly high activity or differential activities. One example of the latter is represented by the cis- and trans-isomers of 2-diphenylmethyl-5-(4-fluorobenzylamino)piperidine, prepared in racemic form. The cis isomer showed a selectivity ratio of 93.7 SERT/DAT, while the trans isomer showed a 6.28 selectivity ratio. Individual enantiomers are expected to exhibit yet higher activity and selectivity.

Having generally described this invention, a further understanding can be obtained by reference to certain specific examples which are provided herein for purposes of illustration only and are not intended to be limiting unless otherwise specified.

Target compounds are prepared as free bases or salts, e.g. hydrochloride, hydrobromide, oxalate, tartrate, etc. Characterization of the compounds is carried out using standard high field NMR, mass spectra, optical rotation, etc. Purity of the compounds are measured by elemental analysis, TLC or HPLC. A purity of >98% is preferred for the biological analysis of these compounds.

The rat DAT was labeled with [³H]Win 35,428 and the rat SERT with [³H]citalopram. Both binding assays were carried out under the same conditions with striatal tissue from male, young adult Sprague-Dawley rats, as described in M. E. A. Reith et al., “Structural Requirements for Cocaine Congeners to Interact With Dopamine and Serotonin Uptake Sites in Mouse Brain and to Induced Stereotyped Behavior”, BIOCHEM. PHARMACOL., 1986, 35, 1123-1129 and A. K. Dutta et al., “Structure-Activity Relationship Studies of Novel 4-[2-[Bis(4-fluorophenyl)methoxy]ethyl]-1-(3-phenylpropyl)piperidine Analogs: Synthesis and Biological Evaluation at the Dopamine and Serotonin Transporter Sites”, J. MED. CHEM., 1996, 39, 749-756. Briefly, rat striatal membranes were incubated with radioligand and inhibitor for 2 h on ice in a sodium phosphate buffer at a final Na⁺ concentration of 30 nM, pH 7.4, at room temperature. The assays were terminated by filtration through glass fiber filtermats (Wallac, Inc., Gaithersburg, Md.), presoaked in 0.05% (v/v) polyethyleneimine, with a MACH3-96 Tomtec harvester (Wallac, Inc.). Filters were assayed for radioactivity in a Microbeta Plus liquid scintillation counter (Wallac, Inc.).

Uptake of [³H]dopamine into HEK-293-hDAT cells was measured in suspended, intact cells by general techniques previously described. M. C. Ritz et al., “Cocaine Inhibition of Ligand Binding at Dopamine, Norpinephrine and Serotonin Transporters: A Structure-Activity Study”, LIFE. SCI., 1990, 46, 635-645; M. J. Kaufman et al., SYNAPSE, 1991, 9, 43-49. Briefly, cells were preincubated with inhibitor for 15 minutes at room temperature in the same tropolone-containing buffer as described above; [³H]dopamine was added and the incubation continued for another 8 minutes. Termination of the assay consisted of addition of ice-cold buffer and rapid filtration through Whatman GF/C glass fiber filters, presoaked in 0.05% (w/v) poly-L-lysine, with a Brandel 24-pin harvester (Brandel, Inc. Gaithersburg, Md.). Radioactivity on filters was estimated by liquid scintillation counting (Beckman LS6000IC, Beckman Instruments, Inc., Fullerton, Calif.).

All compounds were dissolved in dimethylsulfoxide (DMSO) and diluted to 10% (v/v) DMSO. Additions from the latter stocks resulted in a final concentration of DMSO of 0.5%, which by itself did not interfere with radioligand binding or uptake. After initial range-finding experiments, at least five concentrations of the test compound were studied, spaced evenly around its IC₅₀ value. The latter was estimated by non-linear computer curve fitting procedures as described previously.

The DAT, SERT, and NET activities for these compounds make them useful in numerous ways. For example, radioligand version of these disclosed compounds will find applications as imaging agents for DAT in the CNS for SPECT and PET imaging studies. Such imaging may be used in diagnosing Parkinson's disease.

In addition, the compounds may serve as ligands for the DAT, SERT, and NET for use as comparative or base ligands when testing new candidate CNS drugs. Most importantly, however, the compounds of the subject invention, as shown by their binding affinities at low concentration, will have utility in treating CNS disorders such as drug addiction, particularly the effects of cocaine and PCP administration, and potentially the effects of administration of other psychoactive drugs, both legal and illicit. The compounds may be used to treat cocaine addiction, for example. The subject compounds also show utility, based on the in vitro studies described herein, for administration to patients suffering from Parkinson's disease and other related disorders. The compounds further have utility as antidepressants, and in treating other neurological disorders related to those above.

The studies performed to date and disclosed herein thus support the use of the presently claimed compounds in the treatment of CNS disorders in mammalian species, particularly in humans. The effective dosage will vary depending upon the particular disorder being treated. In general, the administration will be such that a concentration will be present in brain tissue and/or fluids which cause measurable binding to the DAT, SERT, or NET. This binding may be assessed by traditional techniques, including using radiolabeled compounds of the present invention or by using the compounds of the present invention to displace other radiolabeled ligands. Conventional techniques such as SPECT and PET may be used in assaying binding.

In general, the concentration of the compounds in the blood or plasma should range from about 1% of the IC₅₀ concentration for the respective transporter, as measured herein, to about 1000% of this concentration, more preferably from 5% to 400%, yet more preferably from 10% to 200%.

The administration may be in any pharmaceutically acceptable form, for example as a liquid containing the active compound dissolved in a suitable solvent or dispersed or emulsified in a liquid; intravenously; as a solid in tablet or capsule form; parenterally as an injected liquid, or transdermally from a transdermal patch. Each formulation may contain usual pharmaceutically acceptable additives, including but not limited to flavorants, odorants, tabletting aids, solubility enhancers, permeability enhancers, surfactants, fillers, etc. In addition, the compounds may be reacted with suitable salt formers of their pharmaceutically acceptable salts, including but not limited to acetates, formates, oxalates, tartrates, hydrochlorides, hydrobromides, hydrogen sulfates, etc.

The expected useful dosage when administered orally is from to 0.01 mg to 100 mg per kilogram of body weight, more preferably from 0.1 mg to 50 mg, yet more preferably 0.2 mg to 30 mg. Total dosage for the average adult may range from 5 mg to 500 mg, preferably 10 mg to 250 mg, and most preferably 10 mg to 150 mg. The actual dosage can be determined readily by conventional methodology.

Target compounds are prepared as free bases or salts, e.g. hydrochloride, hydrobromide or oxalate. Characterization of the compounds is carried out using standard high field NMR, mass spectra, optical rotation, etc. Purity of the compounds are measured by elemental analysis, TLC or HPLC. A purity of >98% is preferred for the biological analysis of these compounds. Several general synthetic pathways have been used herein. Other synthetic methods well known to the synthetic organic chemist may be used to prepare the compounds of the subject invention, or to derivatize these compounds.

Synthesis of Intermediates 1-(Methoxycarbonyl)-4-[(2-Diphenylmethoxy)ethyl]piperidine

The solution of 4-[2-(Diphenylmethoxy)ethyl]-1-(phenylmethyl)piperidine (4.62 g, 11.82 mmol) and methyl chloroformate (2.60 g, 23.53 mmol) in benzene (60 ml) was refluxed for 6 hours. After T.L.C. showed the completion of reaction, the solvent was removed under vacuo to give a viscous liquid 1-(methoxycarbonyl)-4-[(2-diphenylmethoxy)ethyl]piperidine, 4.17 g (99% yield). ¹H NMR (CD₃Cl) δ 7.34-7.18 (10H, m, Ar—H), 5.30 (1H, s, Ph₂CHO), 3.67 (3H, s, OCH₃), 3.50-3.46 (2H, t, J=6.0 Hz, OCH₂), 2.77-2.68 (2H, t, J=12.3 Hz, N(CH)₂), 2.62-2.54 (2H, t, J−12.0 Hz, N(CH)₂), 1.67-1.57 (5H, m), 1.26-1.07 (2H, m).

4-[(2-Diphenylmethoxy)ethyl]piperidine

1-(methoxycarbonyl)-4-[(2-diphenylmethoxy)ethyl]piperidine (4.17 g, 11.81 mmol) was dissolved in ethanol (100 ml), KOH (2.5 g) was added into the solution. The reaction solution was refluxed for 3 days. The solvent was evaporated and EtOAc was added. The EtOAc solution was washed by brine, dried over Na₂SO₄, and evaporated to give a crude product, which was purified by chromatography (EtOAc/MeOH/Et₃N=100/5/2) to give a white solid 4-[(2-diphenylmethoxy)ethyl]piperidine, 2.80 g (80% yield). ¹H NMR (CD₃Cl) δ 7.35-7.19 (10H, m, Ar—H), 5.31 (1H, s, Ph₂CHO), 3.50-3.46 (2H, t, J=6.0 Hz, OCH₂), 3.08-3.04 (2H, bd, J=2.3 Hz, N(CH)₂), 2.77-2.68 (2H, t, J=12.6 Hz), 2.62-2.54 (2H, t, J=12.3 Hz, N(CH)₂), 1.82-1.57 (5H, m), 1.14-1.02 (2H, m). Anal. [C₂₀H₂₅NO.2.0H₂O] Calculated: C, 79.90; H, 8.58; N, 4.66. Found: C, 79.86; H, 8.59; N, 4.70.

N-Benzhydryloxyphthalimide

A solution of 1-chloro-1,1-diphenylmethane (3.42 g, 16.93 mmol), N-hydroxyphthalimide (2.30 g, 14.11 mmol) and Et₃N (3.0 ml) in DMF (50 ml) was stirred at 60° C. under N₂ for 8 hours. After the reaction mixture was cooled to room temperature, water (100 ml) was added. The mixture was extracted with Et₂O. The combined organic phase was dried over Na₂SO₄. After evaporation of the solvent, the crude product was purified by chromatography(Hexane/Benzene/EtOAc=20/10/3) to give a white solid, 3.95 g (85% yield). ¹H NMR (CD₃Cl) δ 7.72-7.63 (1H, m), 7.56-7.53 (1H, m), 7.40-7.24 (12H, m), 5.85 (1H, s, Ph₂CH).

O-Benzyhydrylhydroxylamine

N-Benzhydryloxyphthalimide (1.03 g, 3.14 mmol) was dissolved in EtOH (20 ml). NH₂NH₂ (0.3 ml) was added into the EtOH solution. After the reaction mixture was stirred at room temperature for 0.5 h., EtOH was removed under vacuo and EtOAc (60 ml) was added. The mixture was filtered. The solution was collected and dried over Na₂SO₄. After the evaporation of solvent, the crude product was purified by chromatography(Hexane/EtOAc=5/1) to give a viscous oil 0.31 g (50% yield). ¹H NMR (CD₃Cl) δ 7.34-7.26 (10H, m, AR—H), 5.65 (1H, s, Ph₂CH).

1-[(4-Fluorophenyl)methyl]-4-piperidinemethanol

Dry THF (50 ml) was added dropwise into lithium aluminum hydride (0.7 g) under N₂ in ice bath. 1-[(4-Fluorophenyl)methyl]-4-(ethoxycarbonyl)piperidine (1.21 g, 4.57 mmol) in dry THF (10 ml) was added dropwise into the LAH suspension solution. The reaction mixture was refluxed for 2 hours. Saturated NaOH/H₂O (3 ml) was added dropwise and the reaction cooled by an ice bath. The mixture was filtered. The solution was dried over Na₂SO₄ and evaporated to produce 11 0.98 g (98% yield). ¹H NMR (CD₃Cl) δ 7.36-7.26 (2H, m, Ar—H), 7.07-6.96 (2H, m, Ar—H), 4.66 (1H, s, OH), 3.50-3.48 (2H, d, J=6.0 Hz, CH₂OH), 3.46 (2H, s, F-PhCH₂), 2.90-2.87 (2H, bd, J=11.1 Hz, N(CH)₂), 1.99-1.91 (2H, dt, J=1.8, 11.8 Hz, N(CH)₂), 1.73-1.68 (3H, m), 1.34-1.22 (2H, m).

1-[(4-Fluorophenyl)methyl]-4-piperidinecarboxaldehyde

A solution of oxylyl chloride (0.59 ml, 3.95 mmol) in CH₂Cl₂ (20 ml) was cooled to −78° C. DMSO (0.95 ml, 13.38 mmol) was added dropwise into the oxylyl chloride solution. The reaction mixture was stirred for 5 minutes, and 1-[(4-fluorophenyl)methyl]-4-piperidinemethanol (0.99 g, 4.46 mmol) in CH₂Cl₂ (20 ml) was added dropwise into the reaction solution. Stirring was continued for an additional 20 minutes. Et₃N, 8.0 ml was added and the reaction mixture was stirred for 10 minutes and then allowed to warm to room temperature. Water (50 ml) was added and the mixture was extracted with CH₂Cl₂. The combined CH₂Cl₂ solution was dried over Na₂SO₄. The evaporation of solvent gave an oil, 0.77 g (79% yield). ¹H NMR (CD₃Cl) δ 9.65 (1H, s, CHO), 7.30-7.24 (2H, m, Ar—H), 7.00-6.97 (2H, m, Ar—H), 3.46 (2H, s, pFPhCH₂), 2.81-2.76 (2H, m, N(CH)₂), 2.30-2.20 (1H, m, CHCHO), 2.14-2.06 (2H, dt, J=2.1, 11.3 Hz, N(CH)₂), 1.92-1.86 (2H, dd, J=3.5, 13.5 Hz), 1.74-1.62 (2H, m).

4-[(2-Diphenylethyl)aminocarbonyl]-1-[(4-fluorophenyl)methyl]piperidine

1-[(4-Fluorophenyl)methyl]-4-(ethoxycarbonyl)piperidine (0.68 g, 2.72 mmol) was converted into its carboxylic acid, which was then reacted with 2,2-diphenylethyl amine (0.67 g, 3.40 mmol), EDCI (0.76 g, 3.95 mmol), and HOBT (0.62 g, 4.59 mmol) to produce 4-[(2-diphenylethyl)aminocarbonyl]-1-[(4-fluorophenyl)methyl]piperidine, 0.84 g (75% yield)(procedure D). ¹H NMR (CD₃Cl) δ 7.36-7.20 (12H, m, Ar—H), 7.01-6.95 (2H, m, Ar—H), 5.39 (1H, bs, NH), 4.21-4.15 (1H, t, J=7.8 Hz, Ph₂CH), 3.91-3.86 (2H, t, J=7.5 Hz, CH ₂NH), 3.41 (2H, s, p-FPhCH₂), 2.84-2.80 (2H, d, J=11.4 Hz, N(CH)₂), 1.96-1.87 (3H, m, NHCOCH, NH(CH)₂), 1.65-1.58 (4H, m).

4-[(Bis(4-fluorophenyl)ethylamino)carbonyl-1-(phenylethyl)piperidine

1-(phenylethyl)-4-(ethoxycarbonyl)piperidine (0.25 g, 0.95 mmol) was converted into its carboxylic acid, which was then reacted with bis(4-fluorophenyl)methyl amine (0.25 g, 1.14 mmol), EDCI (0.25 g, 1.27 mmol), HOBT (0.20 g, 1.48 mmol) in Et₃N (1.5 ml) and CH₂Cl₂ (20 ml) to produce 4-[(bis(4-fluorophenyl)ethylamino)carbonyl-1-(phenylethyl)piperidine, 0.32 g (74% yield)(procedure E). ¹H NMR (CD₃Cl) δ 7.29-7.03 (10H, m, Ar—H), 7.05-6.99 (3H, m, Ar—H), 6.22-6.20 (1H, d, J=7.8 Hz), p-FPh₂CH), 6.00-5.97 (1H, d, J=7.5 Hz, NH), 3.08-3.04 (2H, bd, J=11.4 Hz, N(CH)₂), 2.83-2.78 (2H, d), 2.62-2.57 (2H, m), 2.25-2.15 (1H, m, NCOCH), 2.10-2.03 (2H, t, J=11.4 Hz, N(CH)₂), 1.96-1.81 (4H, m).

4-[(1-Phenylethyl)aminocarbonyl]methyl-1-[(4-fluorophenyl)methyl]piperidine

1-[(4-fluorophenyl)methyl]-4-[(ethoxycarbonyl)methyl]piperidine (0.55 g, 1.97 mmol) was refluxed in CF₃CO₂H/HCl/H₂O (1:1:1) 10 ml to give the corresponding acid, which was then reacted with 1-phenylethylamine (0.29 g, 2.40 mmol), EDCI (0.56 g, 2.97 mmol) and HOBT (0.40 g, 2.96 mmol) in CH₂Cl₂ (10 ml) to produce a solid, 0.33 g (50% yield)(procedure D). ¹H NMR (CD₃Cl) δ 7.35-7.23 (7H, m, Ar—H), 7.00-6.94 (2H, t, J=8.4 Hz, Ar—H), 5.83-5.80 (1H, bd, J=7.5 Hz, NH), 5.15-5.10 (m, 1H, PhCHMe), 3.42 (s, 2H, p-PhCH₂N), 2.83-2.78 (m, 2H, N(CH)₂), 2.07-2.05 (2H, d, J=7.2 Hz, CH₂CO), 1.99-1.89 (2H, m), 1.86-1.78 (1H, m), 1.71-1.61 (2H, t, J=15 Hz), 1.48-1.45 (3H, d, J=6.9 Hz, Me), 1.33-1.21 (2H, m).

Synthesis of 2-(Diphenylcyanomethyl)-5-nitropyridine

To a mixture of 1.0 g 2-chloro-5-nitropyridine (6.3 mmol), 1.33 g diphenylacetonitrile (6.9 mmol, 1.1 equiv) and 700 mg tetrabutylammonium fluoride (3.15 mmol, 0.5 equiv) in 3 mL toluene was added dropwise 1.5 mL 50% aqueous NaOH. After 30 min, no starting materials remained by TLC (hexane/EtOAc). The mixture was filtered through a short plug of silica to remove tars, evaporated and chromatographed (SiO₂; hexane/EtOAc). The crude product was a slightly yellow oil which was recrystallized from MeOH to furnish the title compound (1.7 g, 86%) as colorless plates. mp 94-9° C. ¹H NMR (CDCl₃; 300 MHz) 7.20-7.29 (5H, m), 7.35-7.42 (5H, m), 7.54 (1H, d, J=8.7 Hz, H-3), 8.49 (1H, dd, J=3 and 9 Hz, H-4), 9.60 (1H, d, J=2.4 Hz, H-6). ¹³C NMR (CDCl₃; 300 MHz) 60.19, 121.65, 123.77, 128.87, 129.09, 129.33, 132.52, 138.46, 143.49, 145.31, 164.99. Elemental analysis calculated for C₁₉H₁₃N₃O₂: C, 72.38; H, 4.13; N, 13.33. Found: C, 72.35; H, 4.08; N, 13.25.

Synthesis of 2-(Diphenylacetamidomethyl)-5-nitropyridine

A mixture of 5.0 g 2-(diphenylcyanomethyl)-5-nitropyridine (15.8 mmol) was added to a magnetically-stirred, room temperature solution of 40 mL conc. H₂SO₄ diluted with 10 mL H₂O. The mixture was then heated to 90° C. until all starting material consumed by TLC (−2 hr). The dark solution was then poured onto crushed ice and water and stirred for 1 hr, the crude title compound precipitates. The mixture was extracted thrice with EtOAc and these were pooled, dried (MgSO₄, with filtration through short plug of Celite) and evaporated. Dry-column chromatography (silica; hexane/EtOAc/MeOH) furnished the title compound (4.74 g, 90%) as a amorphous tan solid. mp 160-4° C. ¹H NMR (CDCl₃; 300 MHz) 5.9 (1H, bs, NH), 7.05-7.1 (4H, m, ArH), 7.26 (1H, d, J=2.4 and 6.3 Hz, H-4), 9.43 (1H, d, J=1.8 Hz, H-6. ¹³C NMR (CDCl₃; 400 MHz) 126.78, 128.02, 128.64, 130.25, 131.68, 142.09, 143.43, 169.44, 173.99. Elemental analysis calculated for C₁₉H₁₅N₃O₃; C, 68.47; H, 4.50; N, 12.61. Found: C, 68.49; H, 4.55; N, 12.60.

Synthesis of Diphenyl-(5-amino-2-pyridyl)acetamide

A mixture of 8.86 g of diphenyl-(5-nitro-2-pyridyl)acetamide (26.5 mmol) in 50% EtOH/glacial AcOH with 100 mg platinum (V) oxide was shaken on a Parr hydrogenator (30 psi H₂) for 3 hr. The mixture was filtered through a bed of Celite, then the ethanol was evaporated under reduced pressure. The mixture was then basified with K₂CO₃ and extracted with EtOAc (4×), dried (MgSO₄), filtered through Celite again and evaporated. The remaining solid was recrystallized from hexane/EtOAc/MeOH to furnish the title compound (7.9 g, 98%) as a tan crystal. mp 215-20° C. ¹H NMR (CDCl₃; 300 MHz) δ 3.85 (2H, bs, NH), 5.88 (1H, bs, CONH), 6.54 (1H, d, J=8.4 Hz), 6.84 (1H, dd, J=3 and 8.7 Hz), 7.01-7.06 (4H, m), 7.24-7.32 (6H, m), 8.11 (1H, d, J=2.4 Hz, H-6), 9.57 (1H, bs, CONH). Elemental analysis calculated for C₁₉H₁₇N₃O.0.25H₂O: C, 74.15; H, 5.69; N, 13.67. Found: C, 74.06; N, 5.69; H, 13.78.

Synthesis of 2-Diphenylmethyl-5-aminopyridine

A mixture of 5.28 g diphenylmethyl-(5-amino-2-pyridyl)acetamide (17.4 mmol) and 150 mL 37% HCl under a N₂ atmosphere was refluxed until all starting material was consumed by TLC (˜18 hr). The mixture was then cooled and poured into 300 g ice and H₂O and basified with K₂CO₃. The mixture was extracted thrice with EtOAc (150 mL), dried (MgSO₄) and evaporated to a green oil that solidified. This was chromatographed (SiO₂; hexane/EtOAc) to furnish the title compound (4.09 g, 90%) as a tan crystalline solid. mp 1304° C. ¹H NMR (CDCl₃; 300 MHz) δ 3.52 (2H, bs, NH), 5.61 (1H, s, CH(C₆H₅)₂), 6.83-6.91 (2H, m, ArH), 7.15-7.32 (10H, m, ArH), 8.08 (1H, d, J=2.4 Hz, H-6). ¹³C NMR (CDCl₃; 300 MHz) δ8.61, 122.38, 123.98, 126.55, 128.57, 129.56, 137.31, 140.77, 143.64, 153.39. Elemental analysis calculated for C₁₈H₁₆N₂; C, 83.08; H, 6.15; N, 10.77. Found: C, 82.82; H, 6.30; N, 10.81.

Synthesis of racemic cis- and trans-2-Diphenylmethyl-5-aminopiperidine

To a solution of 454 mg 2-diphenylmethyl-5-aminopyridine dihydrochloride salt (3.83 mmol) and 20 mL MeOH was added 50 mg platinum (IV) oxide and the mixture was shaken at room temperature under a H₂ atmosphere (60 psi) for 10 hr. The mixture was then filtered through Celite and the MeOH was evaporated. The remaining residue was diluted with saturated K₂CO₃ and extracted with CH₂Cl₂ (5×). The extracts were pooled, dried (MgSO₄) and evaporated to a colorless oil. The oil was chromatographed (SiO₂; CH₂Cl₂/MeOH/triethylamine) to furnish 300 mg (82%) of the title compounds as a colorless oil. The oil solidified upon addition of EtO₂. A sample of this mixture of diastereomers was separated by PTLC (SiO₂; hexanes/EtOAc/MeOH). Eluting first: racemic cis-2-diphenylmethyl-5-aminopiperidine, ¹H NMR (CDCl₃; 400 MHz) δ 1.35-1.45 (2H, m, H-3), 1.55-1.65 (2H, m, H-4), 2.08 (3H, bs, NH), 2.77-2.82 (2H, s, H-6) 3.0 (1H, m, Σ³J=13 Hz, H-5eq), 3.25 (1H, dt, ³J=4.0 and 8.8 Hz, H-2ax), 3.81 (1H, d, ³J=10.4 Hz, CH(C₆H₅)₂), 7.1-7.4 (10H, m, ArH). Eluting second: racemic trans-2-diphenylmethyl-5-aminopiperidine, ¹H NMR (CDCl₃; 400 MHz) δ 1.1-1.25 (2H, m, H-3ax, H-4ax), 1.55-1.6 (1H, m, H-3 eq), 1.9-1.96 (1H, m, H-4 eq), 2.13 (3H, bs, NH), 2.35 (1H, t, ²J and ³J=10.8 Hz, H-6ax), 2.85 (1H, m, Σ³J=38 Hz, H-5ax), 3.11 (1H, d, ²J=9.2 Hz, H-eq), 3.19 (1H, t, ³J=10.8 Hz, H-2ax), 3.69 (1H, d, ³J=10 Hz, CH(C₆H₅)₂), 7.15-7.4 (10H, m, ArH). The ¹H NMR (CDCl₃; 400 MHz) of the purified, unseparated mixture of the title compounds showed the ratio of 60 cis:40 trans based on integration (CH(C₆H₅)₂).

EXAMPLES Example 1 4-[2-(Diphenylmethoxy)ethyl]-1-[(3-fluorophenyl)methyl]piperidine

A mixture of 4-[(2-Diphenylmethoxy)ethyl]piperidine 4 (58 mg, 0.19 mmol), 3-fluorobenzyl chloride (51 mg, 0.35 mmol), Et₃N (0.5 ml), and anhydrous K₂CO₃ (0.3 g) in DMF (10 ml) was stirred at 65° C. overnight. The reaction mixture was diluted with 30 ml water and extracted with Et₂O. The combined organic phase was dried over Na₂SO₄ and evaporated to give a crude product, which was purified by chromatography (EtOAc/Hexane=1/3) to give 4-[2-(diphenylmethoxyethyl]-1-[(3-fluorophenyl)methyl]piperidine, a viscous liquid 62 mg (79% yield) (“Procedure A”). ¹H NMR (CD₃Cl) δ 7.34-7.20 (10H, m, 2Ph), 7.11-7.03 (3H, m, m-FPh), 6.95 (1H, m, m-FPh), 5.31 (1H, s, Ph₂CH), 3.45-3.44 (2H, t, J=6.6 Hz, OCH₂), 3.44 (2H, s, m-FPhCH₂), 2.84-2.80 (2H, bd, J=11.1 Hz, N(CH)₂), 1.97-1.89 (2H, t, J=11.4 Hz, N(CH)₂), 1.63-1.51 (4H, m), 1.49-1.44 (1H, m), 1.29-1.21 (2H, m). The free base was converted into its oxalate salt, m.p.=150-151° C. Anal. [C₂₇H₃₀NOF.(COOH)₂.0.3 H₂O] Calculated: C, 69.79; H, 6.58; N, 2.80. Found: C, 69.87; H, 6.80; N, 2.76.

Example 2 4-[2-(Diphenylmethoxy)ethyl]-1-[(3,4-difluorophenyl)methyl]piperidine

4-[(2-Diphenylmethoxy)ethyl]piperidine 4 (0.12 g, 0.42 mmol) was reacted with (3,4-difluoro)benzyl bromode (0.17 g, 0.82 mmol), Et₃N (0.5 ml), and K₂CO₃ (0.6 g) in dry DMF (10 ml) to give 4-[2-(diphenylmethoxy)ethyl]-1-[(3,4-difluorophenyl)methyl]piperidine, 0.15 g (86% yield), as a viscous liquid (procedure A). ¹H NMR (CD₃Cl) δ 7.34-6.99 (13H, m, Ar—H), 5.31 (1H, s, Ph₂CH), 3.49-3.45 (2H, t, J=6.3 Hz, OCH₂), 3.85 (s, 2H, NCH₂Ph), 2.80-2.77 (2H, d, J=11.4 Hz, N(CH)₂), 1.95-1.87 (2H, t, J=11.4 Hz, N(CH)₂), 1.63-1.55 (4H, m), 1.50-1.42 (1H, m), 1.28-1.15 (2H, m). The free base was converted into its oxalate salt, m.p.=158-159° C. Anal. [C₂₇H₂₉NOF₂.(COOH)₂] Calculated: C, 68.07; H, 6.11; N, 2.73; Found: C, 68.18; H, 6.13; N, 2.73.

Example 3 4-[2-(Diphenylmethoxy)ethyl]-1-[((4-trifluoromethyl)phenyl)methyl]piperidine

4-[(2-Diphenylmethoxy)ethyl]piperidine 4 (0.11 g, 0.37 mmol) was reacted with (4-trifluoromethyl)benzyl chloride (0.14 g, 0.72 mmol), Et₃N (0.5 ml) and K₂CO₃ (0.5 g) in DMF (10 ml) to give 4-[(diphenylmethoxy)ethyl]-1-[((4-trifluoromethyl)phenyl)methyl]piperidine, 0.15 g (92% yield), as a viscous liquid (procedure A). ¹H NMR (CD₃Cl) δ 7.64-7.47 (4H, m, CF₃Ph), 7.34-7.23 (10H, m, 2Ph), 5.31 (s, Ph₂ CH), 3.52 (2H, s, p-FPhCH₂), 3.49-3.45 (2H, t, J=6.3 Hz, OCH₂), 2.84-2.80 (2H, d, J=11.1 Hz, N(CH)₂), 2.00-1.92 (2H, t, J-11.1 Hz, N(CH)₂), 1.63-1.55 (4H, m), 1.49-1.42 (1H, m), 1.27-1.15 (2H, m). The free base was converted into its oxalate salt, m.p.=149-150° C. Anal. [C₂₇H₃₀NOF₃.(COOH)₂.0.70H₂O] Calculated: C, 64.77; H, 6.05; N, 2.51. Found: C, 65.15; H, 6.46; N, 2.40.

Example 4 4-[2-(Diphenylmethoxy)ethyl]-1-[(4-cyanophenyl)methyl]piperidine

4-[(2-Diphenylmethoxy)ethyl]piperidine 4 (0.15 g, 0.52 mmol) was reacted with 4-cyanobenzyl bromide (0.18 g, 0.92 mmol), Et₃N (0.5 ml) and K₂CO₃ (0.7 g) in DMF 10 ml to give 4-[2-(diphenylmethoxy)ethyl-1-[(4-cyanophenyl)methyl]piperidine, 0.17 g (84% yield), as a white solid (procedure A). ¹H NMR (CD₃Cl) δ 7.61=7.58 (2H, d, J=7.5 Hz, Ar—H), 7.45-7.42 (2H, d, J=7.5 Hz, Ar—H), 7.33-7.22 (10H, m, Ar—H), 5.31 (1H, s, Ph₂CHO), 351 (2H, s, p-CNPhCH₂), 3.50-3.46 (2H, t, J=6.0 Hz, OCH CH₂CH₂), 2.81-2.77 (2H, bd, J=10.8 Hz, N(CH)₂), 2.00-1.93 (2H, t, J=11.1 Hz, N(CH)₂), 1.65-1.56 (4H, m), 1.52-1.46 (1H, m, OCH₂CH₂ CH), 1.30-1.18 (2H, m). The free base was converted into its oxalate salt, m.p.=120-121° C. Anal. [CH₂₈H₃₀N₂O).(CO₂H)₂.0.26H₂O] Calculated: C, 71.32; H, 6.48; N, 5.54. Found: C, 71.32; H, 6.69; N, 5.39.

Example 5 4-[2-(Diphenylmethoxy)ethyl]-1-[(phenylmethyl)carbonyl]piperidine

A solution of phenylacetic acid (0.1 g, 0.82 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimidehydrochloride (EDCI) (0.17 g, 0.88 mmol), and 1-hydroxybenzotriazole (HOBT) (0.11 g, 0.88 mmol) in Et₃N (1 ml) and dry CH₂Cl₂ (10 ml) was stirred at room temperature for 1 hour. 4-[(2-diphenylmethoxy)ethyl]piperidine 4 (0.12 g, 0.41 mmol) in CH₂Cl₂ (5 ml) was added. The solution was stirred at room temperature overnight. The solvent was removed in vacuo, the residue was dissolved in EtOAc. The organic phase was washed with 5% citric acid aqueous solution, followed by saturated NaHCO₃ solution, and dried over Na₂SO₄. The organic extract was evaporated to give a crude product, which was purified by chromatography (EtOAc/Hexane=1/3) to collect a viscous liquid 4-[2-(diphenylmethoxy)ethyl]-1-[(phenylmethyl)carbonyl]piperidine(5e), 0.27 g (96% yield) (“Procedure B”). ¹H NMR (CD₃Cl) δ 7.32-7.25 (15H, m, Ar—H), 5.29 (1H, s, Ph₂CHO), 4.62-4.58 (1H, d, J=12.6 Hz, NCH), 3.84-3.79 (1H, d, J=13.2 Hz, NCH), 3.72 (2H, s, PhCH₂), 3.47-3.43 (2H, t, J=6.2 Hz, OCH₂), 2.96-2.88 (1H, t, J=12.6 Hz, NCH), 2.58-2.50 (1H, t, J=12.3 Hz, NCH), 1.68-1.52 (3H, m), 1.27-1.19 (2H, m), 1.10-1.03 (1H, m), 0.89-0.081 (1H, m). Anal. [C₂₈H₃₁O₂N.0.12H₂O] Calculated: C, 80.90; H, 7.51; N, 3.37. Found: C, 80.87; H, 7.50; N, 3.27.

Example 6 4-[2-(Diphenylmethoxy)ethyl]-1-[((4-methylsulfonylamino)phenyl)methyl]piperidine

4-[(2-Diphenylmethoxy)ethyl]-1-[((4-amino)phenyl)methyl]piperidine (0.11 g, 0.29 mmol) was dissolved in CH₂Cl₂ (5 ml). CH₃SO₂Cl (0.04 g) and Et₃N (0.1 ml) were added. The reaction mixture was stirred at room temperature overnight. The solvent was evaporated and EtOAc 60 ml was added. The organic phase was washed by saturated NaHCO₃/H₂O and brine, and dried over Na₂SO₄. After evaporation, the crude product was purified by chromatography (EtOAc/MeOH=100/1) to give the pure compound 4-[(2-diphenylmethoxy)ethyl]-1-[((4-methylsulfonylamino)phenyl)methyl]piperidine 26 mg (20% yield) ¹H NMR (CD₃Cl) δ 7.41-7.14 (14H, m, Ar—H), 5.31 (1H, s, Ph₂CHO), 3.49-3.34 (4H, m, OCH ₂, NCH ₂Ph), 3.40 (1H, s, NH), 2.98 (3H, s, CH₃SO₂), 2.85-2.81 (2H, bd, J=10.8 Hz, N(CH)₂), 1.97-1.90 (2H, t, J=10.8 Hz, N(CH)₂), 1.64-1.51 (4H, m), 1.50-1.45 (1H, m, O(CH₂)₂ CH), 1.28-1.17 (2H, m). The free base was converted into its oxalate salt, m.p.=122-124° C. Anal. [C₂₈H₃₄N₂O₃S.(COOH).1.15H₂O] Calculated: C, 61.14; H, 6.55; N, 4.75. Found: C, 61.14; H, 6.42; N, 4.71.

Example 7 4-[((2-Diphenylmethoxy)amino)methyl]-1-[(4-fluorophenyl)methyl]piperidine

To a solution of O-Benzyhydrylhydroxylamine 9 (0.25 g, 1.27 mmol) and aldehyde 1-[(4-fluorophenyl)methyl]piperidinecarboxaldehyde (0.28 g, 1.27 mmol) in ClCH₂CH₂Cl (20 ml) was added Na(OAc)₃BH (0.54 g, 2.55 mmol). The reaction mixture was stirred at room temperature overnight. EtOAc 80 ml was added and the solution was washed by saturated NaHCO₃/H₂O and brine. The organic phase was dried over Na₂SO₄ and evaporated to give crude product, which was purified by chromatography (EtOAc/Hexane=1/2) to give a colorless oil, 0.43 g (84% yield). ¹H NMR (CD₃Cl) δ 7.36-7.23 (12H, m, Ar—H), 7.01-6.95 (2H, t, J=7.4 Hz, Ar—H), 3.41 (2H, s, p-F-PhCH₂), 2.82-2.78 (2H, bd, J=11.1 Hz, N(CH)₂), 2.25-2.21 (1H, m, NH), 2.00-1.93 (2H, t, J=10.8 Hz, N(CH)₂), 1.71-1.47 (7H, m). The free base was converted into its oxalate salt, m.p.=154-155° C. Anal. [C₂₆H₂₉FN₂O.(COOH).0.10H₂O] Cacl C, 67.88, H, 6.32; N, 5.65. Found: C, 67.62; H, 5.90; N, 5.51.

Example 8 4-[2-((Diphenylmethyl)amino) ethyl]-1-[(3,4-difluorophenyl)methyl]piperidine

To the solution of 4-[2-diphenylmethyl)aminocarbonyl]methyl-1-[(3,4-difluorophenyl)methyl]piperidine (0.12 g, 0.28 mmol) in dry THF 20 ml was added 1M BH₃/THF (1.0 ml). The reaction solution was refluxed for 6 hours. After the solution was cooled to room temperature, MeOH (5 ml) was added slowly. The solvent was removed under reduced pressure. 10% HCl/MeOH (10 ml) was added into the residue and the solution was refluxed for 1 hour. Solid NaHCO₃ was added after MeOH was evaporated. The mixture was extracted with EtOAc. The combined organic phase was dried over Na₂SO₄ and evaporated to give the crude product, which was purified by chromatography (Hexane/EtOAc/Et₃N=1/2/1%) to a white solid, 0.11 g (90% yield) (“Procedure E”). ¹H NMR (CD₃Cl) δ 7.39-6.99 (13H, m, Ar—H), 4.79 (1H, s, Ph₂CH), 3.39 (2H, s, F₂PhCH₂), 2.80-2.76 (2H, d, J=1.11 Hz, N(CH)₂), 2.60-2.55 (2H, t, J=7.0 Hz, NCH₂), 1.93-1.86 (2H, t, J=1.11 Hz, N(CH)₂), 1.62-1.58 (2H, d, J=12 Hz), 1.49-1.42 (2H, q, J=6.3 Hz, NCH₂ CH ₂), 1.35-1.31 (1H, m, NCH₂CH₂ CH(CH₂)₂), 1.26-1.19 (2H, t, J=12.0 Hz). The free base was converted into its HCl salt, m.p.=280-281° C. Anal: (C₂₇H₃₀N₂F₂.2HCl.0.25H₂O) Calculated: C, 65.12; H, 6.85; N, 5.62. Found: C, 65.13; H, 6.80; N, 5.28.

Example 9 4-[2-((Diphenylmethyl)amino)ethyl]-1-(phenylmethylpiperidine

Compound 4-[2-(diphenylmethyl)aminocarbonyl)methyl-1-(phenylmethyl)piperidine (0.54 g, 1.31 mmol) was reacted with 1M BH₃/THF (5.0 ml) in THF (10 ml) to produce 4-[2-(diphenylmethyl)amino]ethyl-1-(phenylmethylpiperidine, 0.44 g (84% yield)(procedure E). ¹H NMR (CD₃Cl) δ 7.39-7.19 (15H, m, Ar—H), 4.79 (1H, s, PhCH), 3.47 (2H, s, PhCH), 2.86-2.82 (2H, d, J=1.11 Hz, N(CH)₂), 2.59-2.55 (2H, t, J=7.2 Hz, NCH₂), 1.94-1.87 (2H, t, J=11.1 Hz, N(CH)₂), 1.61-1.58 (2H, m), 1.48-1.42 (2H, m), 1.34-1.20 (3H, m). The free base was converted into its HCl salt, m.p.—172-174° C. Anal: (C₂₇H₃₂N₂.2HCl.106H₂O) Calculated: C, 68.05; H, 7.64; N, 5.88.; Pound: C, 68.06; H, 7.82; N, 5.90.

Example 10 4-[2-((Diphenylmethyl)-N-methylamino)ethyl]-1-(4-phenylmethyl)piperidine

A solution of 4-[(2-Diphenylethyl)aminomethyl]-1-[(4-fluorophenyl)methyl]piperidine (0.23 g, 0.59 mmol), formaldehyde (1.0 g, 37%/H₂O) and formic acid (2.0 g, 88%/H₂O) was refluxed for 3 hours. After the reaction solution was cooled to room temperature, the solvent was removed under vacuo. The crude product was purified by chromatography (EtOAc/Hexane=1/2) to give a white solid 0.17 g (71% yield). ¹H NMR (CD₃Cl) δ 7.40-7.16 (12H, m, Ar—H), 7.05-6.95 (2H, t, J=7.4 Hz, Ar—H), 4.31 (1H, s, Ph₂CHN), 3.41 (2H, s, p-FPhCH₂N), 2.80-2.76 (2H, d, J=11.8 Hz, N(CH)₂), 2.36-2.30 (2H, t, J=7.5 Hz, NCH₂), 2.11 (3H, s, NCH₃), 1.91-1.83 (2H, t, J=11.4 Hz, N(CH)₂), 1.54-1.50 (2H, d, J=11.4 Hz), 1.47-1.40 (3H, m, NCH₂ CH₂CH), 1.32-1.10 (2H, m). The free base was converted into its HCl salt, m.p.=260-261° C. Anal. [C₂₈H₃₃N₂F.2HCl.0.50H₂O]] Calculated: C, 67.46; H, 7.29; N, 5.61. Found: C, 67.33; H, 7.19; N, 5.56.

Example 11 4-[[2-(Diphenyl)ethyl]aminomethyl]-1-[(4-fluorophenyl)methyl]piperidine

Compound 4-[(2-diphenylethyl)aminocarbonyl]-1-[(4-fluorophenyl)methyl]piperidine (0.32 g, 13 mmol) was reacted with 1M BH₃/THF (4.0 ml) in THF (20 ml) to produce 4-[(2-diphenylethyl)aminomethyl]-1-[(4 fluorophenyl)methyl]piperidine, 0.25 g (81% yield)(procedure E). ¹H NMR (CD₃Cl) δ 7.32-7.19 (12H, m, Ar—H), 7.00-695 (2H, m, Ar—H), 4.21-4.17 (1H, t, J-7.7 Hz, (Ph₂CH), 3.67 (1H, s, NH), 3.41 (2H, s, p-FPhCH₂), 3.22-3.19 (2H, d, J=7.8 Hz, NHCH ₂CH(Ph)₂), 2.83-2.79 (2H, bd, J=1.1 Hz, N(CH)₂), 2.52-2.50 (2H, d, J=6.6 Hz, NHCH ₂CH), 1.91-1.84 (2H, t, J=11.1 Hz, 1.58-1.54 (2H, d, J-12 Hz), 1.45-1.39 (1H, m, NHCH₂ CH), 1.21-1.14 (2H, t, J=12 Hz). The free base was converted into its HCl salt, m.p.=126-127° C. Anal. [C₂₇H₃₁FN₂O.2HCl] Calculated: C, 62.96; H, 7.31; N, 5.43. Found: C, 62.93; H, 7.19; N, 5.41.

Example 12 4-[(Bis(4-fluorophenyl)methylamino)methyl]-1-[2-(phenyl)ethyl]piperidine

Compound 4-[(2-diphenylethyl)aminomethyl]-1-[(4-fluorophenyl)methyl]piperidine (0.30 g, 0.71 mmol) was reacted with 1M BH₃/THF (4 ml) in NMR (25 ml) to produce a white solid 4-[(bis(4-fluorophenyl)methylamino)methyl]-1-(phenylethyl)piperidine, 0.28 g (96% yield)(procedure E). ¹H NMR (CD₃Cl) δ 7.35-7.18 (10H, m, Ar—HO, 7.00-6.95 (3H, m, Ar—H), 4.74 (1H, S, P—FPh)₂CH), 3.02-2.99 (2H, d, J=10.8 Hz, N(CH)₂), 2.83-2.78 (2H, M), 2.60-2.55 (2H, m), 2.45-2.43 (2H, d, J=6.2 Hz, NHCH ₂CH), 2.04-1.96 (2H, t, J=11.4 Hz, N(CH)₂), 1.78-1.26 (5H, m). The free base was converted into its HCl salt, m.p.=214-215° C. Anal. (C₂₇H₃₀F₂N₂.2HCl.0.50H₂O) Calculated: C, 64.58; H, 6.61; N, 5.57. Found: C, 64.61; H, 6.65; N, 5.43.

Example 13 [[(2-(Diphenyl)ethyl]-N-methylaminomethyl]-1-[(4-fluorophenyl)methyl]piperidine

4-[(2-Diphenylethyl)aminomethyl]-1-[(4-fluorophenyl)methyl]-piperidine 4-[(2-diphenylethyl)aminomethyl]-1-[(4-fluorophenyl)methyl]piperidine (45 mg, 0.11 mmol) was refluxed in formaldehyde (1.0 g) and formic acid (2.0 g, 37%/H₂O) to produce 4-[(2-diphenylethyl)-N=methylaminomethyl]-1-[(4-fluorophenyl)methyl]piperidine, 44 mg (88% yield)(procedure F). ¹H NMR (CD₃Cl) δ 7.28-7.13 (12H, m, Ar—H), 7.02-6.96 (2H, t, J=8.4 Hz, Ar—H), 4.15-410 (1H, t, J=7.5 Hz, Ph₂CH), 3.46 (2H, s, F-PhCH₂), 2.91-2.88 (2H, d, J=7.5 Hz, Ph₂CHCH ₂N), 2.81-2.77 (2H, d, J=1.1 Hz, N(CH)₂), 2.20 (3H, s, CH₃), 2.20-2.17 (2H, d, J=7.5 Hz, NCH ₂CH), 1.90-1.83 (2H, t, J=11.4 Hz, N(CH)₂), 1.52-1.47 (2H d, J=12.9 Hz), 1.54-1.28 (1H, m, NCH₂ CH), 1.14-1.06 (2H, t, J=12.4 Hz). The free base was converted into its oxalate salt, m.p.=144-145° C. Anal. [C₂₈H₃₃N₂F.2(COOH)₂.1.47H₂O]] Calculated: C, 61.68; H, 5.99; N, 4.49. Found: C, 61.65; H, 5.99; N, 4.35.

Example 14 4-[2-[(1-(phenyl)ethyl)amino]ethyl]-1-[(4-fluorophenyl)methyl]piperidine

Compound 4-[(1-phenylethyl)aminocarbonyl]methyl-1-[(4-fluorophenyl)methyl]piperidine (0.33 g, 0.93 mmol) was reacted with 1M BH₃/THF (5.0 ml) to produce a viscous oil, 0.23 g (95% yield)(procedure E). ¹H NMR (CD₃Cl) δ 7.34-=7.21 (5H, m, Ar—H), 7.01-6.95 (2H, t, J=8.4 Hz, Ar—H), 4.09-4.07 (1H, d, J=6.0 Hz, NH), 3.77-3.71 (1H, q, J=6.3 Hz, PhCHMe), 3.42 (2H, s, p-FPhCH₂), 2.82-2.78 (2H, d, J=10.8 Hz; N(CH)₂), 2.55-2.37 (2H, m, NCH₂), 1.91-1.83 (2H, t, J=11.4 Hz, N(CH)₂), 1.59-1.53 (4H, m), 1.44-1.38 (1H, m), 1.36-1.34 (3H, d, J=6.0 Hz, CH₃), 1.25-1.14 (2H, m), The free base was converted into its oxalate salt, m.p.=172-173° C. Anal. [C₂₂H₂₉FN₂.2(COOH)₂] Calculated: C, 59.99; H, 6.39; N, 5.38. Found C, 59.84; H, 6.46; N, 5.29.

Example 15 Synthesis of racemic cis- and trans-2-Diphenylmethyl-5-(4-fluorobenzylamino)piperidine

To a room temperature solution of 420 mg racemic cis- and trans-2-diphenylmethyl-5-aminopiperidine (1.58 mmol), 156 mg 4-fluorobenzaldehyde (0.8 equiv), 94 mg glacial HOAc (1 equiv) in 30 mL 1,2-dichloroethane was added portionwise 119 mg sodium cyanoborohydride (1.2 equiv). The mixture was stirred for 18 hours. Then, H₂O was added and the mixture stirred for 30 min, then acidified with conc HCl, and stirred another 30 min. Then the mixture was basified with conc NaOH and extracted thrice with CH₂Cl₂. The organic phases were collected, dried (MgSO₄) and evaporated. The residue was chromatographed (SiO₂; CH₂Cl₂; MeOH) to purify the mixture (240 mg, 40%) of both diastereomeric pairs. Then this mixture was further chromatographed (SiO₂; 1 hexane; 1 EtOAc: 0.06 triethylamine) to separate the diastereomers. Eluting first: ¹H, NMR, (CDCl₃; 400 MHz) δ 1.3-1.4 (2H, m, H-3), 1.49 (1H, tt, ²J and ³J_(3a)=13.6 Hz; ³J_(3e) and ³J_(5e)=4.0 Hz, H-4ax), 1.65-1.85 (3H, m, H-4ax 2NH), 2.65-2.72 (2H, m, H-5eq, H-6ax), 2.99 (1H, d, ²J=10.4 Hz, H-6 eq), 3.28 (1H, dt, ³J=4.4 and 10.8 Hz, H-2ax), 3.71 (2H, s, CH₂CH₆H₄F), 3.81 (1H, d, ³J=9.6 Hz, CH(C₆H₅)₂), 6.99 (2H, t, ³J=8.4 Hz, ArH ortho F), 7.12-7.39 (12H, m, ArH). Precipitated as bis-hydrochloride salt. mp 60-105° C. Elemental analysis calculated for C₂₅H₂₉N₂FCl₂.0.5H₂O: C, 65.93; H, 6.59; N, 6.15. Found: C, 65.26; H, 6.78; N, 6.49.

Eluting second: racemic trans-2-diphenylmethyl-5-(4-fluorobenzylamino)piperidine (96 mg, 38.5%), ¹H NMR (CDCl₃; 400 MHz) δ 1.17 (2H, qm, ³J=10 Hz, H-3ax and H-4ax), 1.57-1.65 (1H, m, H-3 eq), 1.4-1.7 (bs, NH), 1.9-1.96 (1H, m, H-4 eq), 2.33 (1H, t, ²J and ³J=10.4 Hz, H-6ax), 2.65 (1H, m, Σ³ J=36 Hz, H-5ax), 3.15-3.25 (2H, m, H-2ax, H-6 eq), 3.68 (1H, d, ²J=0.6 Hz, CH(C₆H₅)₂), 3.75 (2H, s, CH₂C₆H₄F), 6.97 (2H, t, ³J=8.8 Hz, ArH Ortho F), 7.1-7.3 (10H, m, ArH), 7.36 (2H, d, ³J=7.6 Hz, ArH meta F). Precipitated as bis-hydrochloride salt. Elemental analysis calculated for C₂₅H₂₉N₂FCl₂.0.5H₂O: C, 65.93; H, 6.59; N, 6.15. Found: C, 65.56; H, 6.89; N, 6.14

Example 16 Synthesis of racemic trans-3-hydroxy-4-[2-diphenylmethoxy)ethyl]-1-[(4-fluorophenyl)methyl]piperidine

To a stirred suspension of

(0.92 g, 1.9 mmol) in THF (10 mL) cooled to 0° C. was added dropwise 1M BH₃ tetrahydrofuran complex (7.7 mL, 7.7 mmol, 4 equiv). Afterwards, the cooling bath was removed and the solution allowed to warm to RT. The mixtures was then refluxed for 12 hr. After cooling to 0° C., H₂O (5.76 mL), EtOH (5.76 mL) and 3N NaOH (15 mL) were added followed by dropwise addition of 30% H₂O₂ (18 mL). The reaction was stirred at 55° C. for 12 hours then cooled to RT and extracted thrice with CH₂Cl₂. The extracts were pooled, dried (MgSO₄) and evaporated to a clear oil. The crude product was chromatographed (SiO₂; 5% MeOH/CH₂Cl₂) to furnish the free base (0.553 mg, 71%). ¹H NMR (CDCl₃) δ 1.34-1.39 (2H, m), 1.59-1.55 (2H, m), 1.81-1.95 (3H, m), 2.72 (1H, d, J=9.9 Hz), 2.98 (1H, d, J=10.5 Hz), 3.42-3.63 (5H, m), 5.37 (1H, s), 6.98 (2H, t, J=9.3 Hz), 7.22-7.35 (12H, m). This was then reacted in EtOH (5 mL) with oxalic acid dihydrate (0.169 g, 1.1 equiv) to furnish the title compound (468 mg, 77%). mp 143-50° C. Elemental analysis calculated for C₂₈H₃₁NO₆F: C, 68.37; H, 6.29; N, 2.75. Found: C, 67.96; H, 6.43; N, 2.63.

Example 17 Synthesis of racemic trans-3-Propionyl-4-[2-(diphenylmethoxy)ethyl]-1-[(4-fluorophenyl)methyl]piperidine

To a solution of 61 mg 3-hydroxy-4-[2-(diphenylmethoxy)ethyl]-1-[(4 fluorophenyl)methyl]piperidine (0.15 mmol) and 21 mg triethylamine (0.23 mmol, 1.5 equiv) in 2 mL CH₂Cl₂ cooled in an ice bath was added dropwise 18 mg propionyl chloride (0.19 mmol, 1.3 equiv) and the reaction was allowed to warm to RT. After 1 hr, the same quantities of triethylamine and propionyl chloride were added. After 1 hr, H₂O was added and the organic layer was separated, dried (MgSO₄) and evaporated. The remaining residue was chromatographed (SiO₂; CH₂Cl₂/MeOH) to yield the title compound as the free base (53 mg, 77%). 1H NMR (CdCl₃ δ 1.1 (3H, t, J=8.1 Hz), 1.26-1.95 (7H, m), 2.26 (2H, q, J=7.2 and 7.5 Hz), 2.71 (1H, d, J=11.7 Hz), 3.02 (1H, d, J=10.5 Hz), 3.41-3.52 (4H, m), 4.67 (1H, t, J=9.6 Hz), 5.31 (1H, s), 6.98 (2H, t, J=9.3 Hz), 7.2-7.4 (12H, m). This was then reacted in a mixture of 2 mL 50% EtOH/Et₂O with oxalic acid dihydrate (15.4 mg, 1.1 equiv) to furnish the title compound. mp ° C. Elemental analysis calculated for C₃₂H₃₆NO₇F.0.5H₂O: C, 67.43; H, 6.41; N, 2.46. Found: C, 67.34; H, 6.43; N, 2.44.

Example 18 Synthesis of racemic 3-Keto-4-[2-(diphenylmethoxy)ethyl]-1-[(4-fluorophenyl)methyl]piperidine

To a solution of oxalyl chloride (0.4 mmol, 0.87 equiv) in CH₂Cl₂ (3 mL) cooled to −78° C. was added dropwise 108 mg dimethylsulfoxide (1.38 mmol, 3 equiv). The mixture was stirred for 10 min and a solution of 236 mg racemic trans-3-hydroxy-4-[2-(diphenylmethoxy)ethyl]-1-[(4-fluorophenyl)methyl]piperidine (0.46 mmol) in CH₂Cl₂ (1 mL) was added dropwise. After stirring 15 min, triethylamine (825 mg, 17.6 equiv) was added and the mixture was allowed to warm to room temperature. All volatiles were evaporated at room temperature and the remaining residue was chromatographed (SiO₂; hexane:EtOAc:MeOH) to furnish the free base (116 mg, 60%), which decomposes at room temperature and must be stored in the cold. ¹H NMR (CdCl₃) α 1.45-1.65 (2H, m), 2.0-2.1 (1H, m), 2.2-2.3 (1H, m), 2.38-2.6 (2H, m), 2.77 (1H, d, J=13.6 Hz), 2.9 (1H, bd, J=13.6 Hz), 3.45-3.55 (4H, m), 5.30 (1H, s), 6.99 (2H, t, J=11.2 Hz), 7.19-7.39 (12H, m). The title compound (125 mg, 50%) was furnished by reacting the free base (205 mg) with oxalic acid dihydrate (62 mg, 1 equiv). mp 104-9° C. Elemental analysis calculated for CH₂₉H₃₀NO₆F: C, 68.64; H, 5.92; N, 2.76. Found: C, 68.34; H, 5.93; N, 2.68.

Example 19 Synthesis of 4-[2-(diphenylmethoxy)ethyl]-1-[(4-iodophenyl)methyl]piperidine

4-[2-(diphenylmethoxy)ethyl]piperidine (0.23 g, 0.77 mmol) was reacted with 4-iodo benzyl bromide (0.76 g, 2.5 mmol) and K₂CO₃ (1.00 g, 7 mmol) in EtOH (10 mL) to give a thick oil, 0.17 g (%). ¹H NMR (300 MHz, CDCl₃): 1.21-1.63 (7H, m), 1.87-1.93 (t, J=11 Hz, 2H, N(CH2)-), 2.79-2.83 (bd, J=12 Hz, 2H, N(CH2)-), 3.41-3.49 (4H, m), 5.31 (s, 1H, Ph2CHO—), 7.05-7.63 (14H, m, ArH). Free base was converted into its oxalate sale, m.p.=160-161° C. Anal. C₂₇H₃₀INO. (COOH)₂.

Biological Testing

We have surprisingly discovered that longer aromatic-alkyl chains in piperidine derivatives give rise to more interaction with the serotonin transporter (SERT), and hence less selectivity (c.f. A. K. Dutta et al., “Structure-Activity Relationship Studies of Novel 4-[2-[Bis(4-fluorophenyl)methoxy]ethyl]-1-(3-phenylpropyl)piperidine Analogs: Synthesis and Biological Evaluation at the Dopamine and Serotonin Transporter Sites”, J. MED. CHEM., 1996, 39, 749-756; A. K. Dutta et al., “Highly Selective, Novel Analogs of 4-[2-(diphenylmethoxy)ethyl]-1-benzylpiperidine For The Dopamine Transporter: Effect of Different Aromatic Substitutions on Their Affinity and Selectivity”, J. MED. CHEM., 1997, 40, 3543; A. K. Dutta et al., Potent and Selective Ligands for the Dopamine Transporter (DAT): Structure-Activity Relationship Studies of Novel 4-[2-diphenylmethoxy)ethyl]-1-(3-phenylpropyl)piperidine Analogs”, J. MED. CHEM., 1998, 41, 699-705). In an effort to explore the effect of electronegative fluorine atoms and the strong electron withdrawing group CN, the compounds of Examples 1-4 were designed and synthesized. The presence of electronegative and electron withdrawing groups enhanced the activity and selectivity of these analogs. These novel compounds, with but a methylene group between the piperidine N-atom and the aryl ring, and with an electronegative aryl substituent, exhibited profound selectivity and potency for the dopamine transporter (DAT). Thus, the compound of Example 4 with a strong electron withdrawing cyano group present in the phenyl ring exhibited remarkable potency and selectivity (IC50, 3.7 nM, SERT/DAT=615, Table 1) for the dopamine transporter. This is a remarkable improvement over the standard reference compound GBR 12909 (IC50, 14 nM, SERT/DAT=6). The compound of Example 2 also showed good potency and more selectivity than GBR 12909 for the DAT (SERT/DAT=122).

The compounds of Examples 8, 9, 11 and 12 (Table 1) employ a 4-(aminoalkyl) linkage between the piperidine ring and the bisaromatic methane portion of the molecule rather than an oxyalkyl linkage. Both Examples 8 and 9 are more potent and selective than the standard GBR 12909 molecule (IC50, 7.0 and 4.5 nM, respectively); SERT/DAT=227 and 347, respectively). The compound 4-[2-(diphenylmethoxy)ethyl]-1-[(4-iodophenyl)methyl]piperidine sets a new standard of activity.

In the compound of Example 11 where the N-atom was relocated to an adjacent position, an interesting effect consisting of the strong affinity for the DAT and the moderate affinity for the SERT was observed. Compound with such dual activity might find unique applications in the medication development for drug abuse and in other neurological disorders, including treatment of depression.

None of these compounds developed in this current series showed any appreciable activity for the norepinephrine transporter (NET), which demonstrates their selectivity for the DAT.

The current novel compounds were also evaluated in the dopamine reuptake inhibition assay which measures the extent of inhibition of dopamine reuptake in the cytosol by these novel compounds. In this regard, cocaine and GBR 12909 are potent DA uptake inhibitors. Ideally, a desirable drug for the treatment of drug addiction should possess less dopamine uptake inhibitory potency and should be less potent than GBR 12909 in that regard, which will increase the drug's chances to act as cocaine antagonist. In this current series of compounds, Table 2, all of the listed results reflect an increased potential of these novel compounds to act as cocaine antagonists than GBR 12909.

TABLE 1 Affinity and Selectivity of Drugs at the Dopamine (DAT), Serotonin (SERT) and Norepinephrine (NET) Transporters DAT, SERT, IC₅₀, NET, IC₅₀, Compound IC₅₀, nM nM nM DAT/SERT CFT 32.3 ± 2.6 GBR 12909 10.6 ± 1.9 132.0 ± 0.0  496 ± 22 1 2 Example 1 23.4 ± 3.8 1145.7 ± 43.4  4 9 Example 2 10.1 ± 0.9   1221 ± 139.4 1 2 2   Example 3 32.1 ± 2.1 2262.8 ± 144.1 7 1 Example 4  3.7 ± 0.6 2277 ± 470 6 1 5   Example 5 2156 ± 54  >1,000 Example 6 26.6 ± 1.4 585.6 ± 29.2 2 2 Example 7 34.4 ± 4.2 625.8 ± 33   691 ± 68 1 9 Example 8  7.0 ± 1.7 1587 ± 160 1,027 ± 94   2 2 7   Example 9  4.5 ± 0.6 1562 ± 208 2,623 ± 173  3 4 7   Example 10 213 ± 3  1659 ± 469   8 Example 11 19.7 ± 1.4 137.2 ± 45.6 1,111 ± 119    7 Example 12 65.3 ± 3.2   1098 ± 245.6 1 7 Example 13  94.0 ± 12.5 2524 ± 230 2 7 Example 14 295.4 ± 40.9   963 ± 38.5     ¹ 751.0 ± 61.6 5855.7 ± 594.6 3-OH² 14.3 ± 3.7 984 ± 94 678 ± 13 6 9 Example 19  0.96 ± 0.16 2920 ± 432 1151 ± 116 3041  ¹4-[((1-phenylethoxy)ethyl]-1-[(4-fluorophenyl)methyl]piperidine ²4-[2-(diphenylmethoxy)ethyl]-1-[(3-hydroxyphenyl)methyl]piperidine ³4-[2-(diphenylmethoxy)ethyl]-1-[(4-iodophenyl)methyl]piperidine

TABLE 2 Inhibition of Dopamine Reuptake in Rat Synaptosome Tissue [3H]DA Inhibition, [3H]DA/ Compound IC50 (nM) Binding, IC50 GBR 12909 6.63 ± 0.43 0.62 Example 2 12.03 ± 1.62  1.33 Example 4 4.58 ± 0.80 1.23 Example 7 16.6 ± 2.8  0.48 Example 6 9.7 ± 1.2 0.36 Example 11 49.56 ± 7.2  2.5 Example 9 20.6 ± 2.5  4.5 Example 8 10.7 ± 1.8  1.5

The activities of racemic cis- and trans-isomers of the compounds of Example 15 were measured. The results are presented below in Table 3. The selectivities with respect to SERT/DAT, NET/DAT and [³H] DA/DT binding ratios are presented in Table 4, along with similar data for cocaine and subject invention Example 11. As can be seen, there is a significant change in the selectivity as between the cis- and trans-isomers. It is expected that the individual stereoisomers of each pair of geometric isomers will also exhibit quite different activity.

TABLE 3 Binding Activity of Cis and Trans at the Dopamine, Serotonin and Norepinephrine Transporters [³H]DA DAT, IC₅₀, uptake Com- nM [³H]WIN SERT, IC₅₀, nM NET, IC₅₀, nM Inhibition, pound 35,428 [³H]citalopram [³H]nisoxetine IC₅₀ (nM) (±)-7a 30.00 ± 0.5 2,813 ± 411 1,349 ± 190   28.9 ± 2.5 (±)-7b  212 ± 20 1,333 ± 102 4,468 ± 1,181 106 ± 10

TABLE 4 Selectivity of Various Ligands for their Binding to the Monoamine Transporters SERT/ NET/ [³H]DA/DAT Compound DAT DAT Binding Cocaine 2.7 6.36 Example 11 6.9 5.6 2.5 (±)-7a 93.7 44.9 0.03 (±)-7b 6.28 21 0.5

TABLE 5 Affinity and Selectivity of Drugs at the Dopamine, Serotonin and norepinephrine Transporters in Rat Striatum DAT, IC₅₀, nM, SERT, [³H]WIN IC₅₀, nM NET, IC₅₀, nM SERT/ Compound 35, 428^(a) [³H]citalopram^(a) [³H]nisoxetine^(a) DAT Cocaine 266 ± 37  737 ± 160 3,526 ± 554  2.7 GBR 12909 10.6 ± 1.9 132 ± 0 496 ± 22 12 Example 16  5.96 ± 1.26  1,108 ± 477  637 ± 114 Example 18  99 ± 18   7,747 ± 1618 6,299 ± 694  Example 17 583 ± 81 177,800 ± 53,00 35,806 ± 

1.-31. (canceled)
 32. Compounds exhibiting CNS activity in mammalian species, said compounds having the formulae:

wherein A in formulae (III) is

and A in formula II is

B is

X is selected from the group consisting of N, —NH—, —NR⁴—, —O—, and —S—; R⁴ is C₁₋₄ alkyl, NH₂, C₁₋₄ hydroxyalkyl, halogenated C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ hydroxyalkenyl, halogenated C₂₋₄ alkenyl, C₂₋₄ and alkynyl, and C₂₋₄ halogenated alkynyl; Y is —NH₂, —OH, ═O, or —O—C(O)—R⁵; l is 0, 1, or 2; n is 1 or 2; m is 1 or 2; o is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, or 4; q is 0, 1, 2, or 3; r is an integer from 0 to 5 R, R¹, and R² are selected from the group consisting of H, F, Cl, Br, I, CN, COOEt, OH, NO₂, NH₂, OR⁵, wherein R⁵ is C₁₋₈ alkyl, C₅₋₆ cycloalkyl, or C₂₋₈ alkenyl or R² is a 5 or 6 membered heterocycle,

and where any carbon of (CH₂)_(m) may be substituted by OR⁷ where R⁷ is C₁₋₁₈ alkyl or C₂₋₁₈ alkylene, or

where R⁸ is C₁₋₁₈ alkyl or C₂₋₁₈ alkylene, or a pharmaceutically acceptable salt or derivative thereof, and wherein in formula (III), A may also be COOCH₃, ═O, CH₃, F, or OH; Z is H or C₁₋₄ alkylene, the C₁₋₄ alkylene groups when present forming a ring structure with X when X is N, and where B may also be H, CH₃, or —CH═CH₂.
 33. A compound of claim 32, wherein l=0, n=2.
 34. A compound of claim 32, wherein l=0, n=2, m=1.
 35. A compound of claim 32, wherein X is —NH— or —O—.
 36. A compound of claim 35, wherein l=0, n=2, m=1, and p=1.
 37. A compound exhibiting CNS activity in mammalian species, having the formula:

wherein A is

and where X is selected from the group consisting of —NH—, —NR⁴—, and —O—; R⁴ is C₁₋₄ alkyl, NH₂, C₁₋₄ hydroxyalkyl, halogenated C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ hydroxyalkenyl, halogenated C₂₋₄ alkenyl, C₂₋₄ and alkynyl, and C₂₋₄ halogenated alkynyl; Y is —OH, OR⁹, NH₂, or NHR⁹ wherein R⁹ is wherein R¹⁰ is C₆₋₂₀ alkyl,

o is 0, 1, 2, 3, or 4; R, R¹ and R² are selected from the group consisting of H, F, Cl, Br, I, CN, COOEt, OH, NO₂, NH₂, OR⁵; wherein R⁵ is C₁₋₈ alkyl, C₅₋₆ cycloalkyl, or C₂₋₈ alkenyl or R² is a 5 or 6 membered heterocycle; p is individually 0, 1, or 2, q is 0, 1, 2, or 3 wherein at least one R² is an electron withdrawing group, and pharmaceutically acceptable salts and derivatives thereof.
 38. The compound of claim 32 having the structure:

and pharmaceutically acceptable salts and derivatives thereof.
 39. The compound of claim 32 having the structure:

wherein A is

and where X is selected from the group consisting of —NH—, —NR⁴—, and —O—; R⁴ is C₁₋₄ alkyl, NH₂, C₁₋₄ hydroxyalkyl, halogenated C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ hydroxyalkenyl, halogenated C₂₋₄ alkenyl, C₂₋₄ and alkynyl, and C₂₋₄ halogenated alkynyl; Y is —H, —NH₂, —OH, ═O, or —O—C(O)—R⁵; wherein R⁵ is C₁₋₈ alkyl, C₅₋₆ cycloalkyl, or C₂₋₈ alkenyl or R⁵ is a 5 or 6 membered heterocycle; m is 1 or 2; p is 0, 1, 2, 3, or 4; R¹ is selected from the group consisting of H, F, Cl, Br, I, CN, COOEt, OH, NO₂, NH₂, OR⁵, wherein R⁵ is C₁₋₈ alkyl, C₅₋₆ cycloalkyl, or C₂₋₈ alkenyl or R² is a 5 or 6 membered heterocycle, and where any carbon of CH₂_(m) may be substituted by OR⁷ where R⁷ is C₁₋₁₈ alkyl or C₂₋₁₈ alkylene, or

where R⁸ is C₁₋₁₈ alkyl or C₂₋₁₈ alkylene, or a pharmaceutically acceptable salt or derivative thereof. 